The management and treatment of myocardial infarction has changed dramatically since the first half of the 20th century, progressing from an era of bed rest and observation, to an emphasis on technology, including hemodynamic monitoring and balloon catheters, to an increased focus on thrombolytic therapy. (Antman and Braunwald, “Acute Myocardial Infarction” in Heart Disease, A Textbook of Cardiovascular Medicine, 6th edition, vol. 2, Braunwald et al., eds, 2001, W. B. Saunders Company, Philadelphia). Therapeutic approaches to treating cardiovascular diseases have evolved tremendously in the last 100 years accompanied by greater understanding of the underlying pathology.
Almost all myocardial infarctions result from coronary atherosclerosis, generally with superimposed coronary thrombosis. Slowly accumulating plaques can be asymptomatic due to the development of collateral vessels. However, atherosclerotic plaques, especially those rich in lipids, are prone to abrupt plaque rupture. Plaque rupture and associated endothelial injury cause the release of mediators such as thromboxane A2, serotonin, adenosine diphosphate, thrombin, platelet activating factor, tissue factor and oxygen-derived free radicals. These mediators promote platelet aggregation and mechanical obstruction often leading to thrombus formation which interferes with blood flow and oxygen supply. Persistent and severe interferences with myocardial oxygen supply can lead to acute myocardial infarction. (See, Rioufol et al., 2002, Circulation 106: 804, Timmis, 2003, Heart 89:1268-72).
The mainstay of atherosclerotic pharmacotherapy has been chronic therapy to prevent or slow the development of atherosclerotic plaques primarily by focusing on lowering LDL or “bad cholesterol” as a therapeutic endpoint. Statin therapy, for example, has greatly contributed to improved cardiovascular health; however, adverse effects such as rhabdomyolysis, remain an impediment. Furthermore, statins do little in an acute situation, for example, to reduce vulnerable, unstable atherosclerotic plaque during an ischemic episode. Acute treatment has largely relied on thrombolytics (such as tPA) and surgical intervention such as percutaneous transluminal coronary angioplasty (PTCA) and coronary artery bypass graft (CABG). While thrombolytics provide relief by decreasing or eliminating an occluding thrombus, they do not alter the underlying pathology. Interventions such as PTCA carry their own risks and are often unsuitable for patients in acute conditions. Hence current pharmacologic therapies do little to help patients once unstable plaque presents as a risk. (See, Newton and Krause 2002, Atherosclerosis S3:31-38).
HDL therapy is emerging as a new treatment paradigm for dyslipidemia and atherosclerosis. Id. Apolipoprotein A-I Milano (Apo A-I Milano) has been of interest due to the paradoxical finding that carriers of the variant form of this apolipoprotein have low HDL (“good cholesterol”) levels and decreased risk of cardiovascular disease. (See, Franceschini et al., 1980, J. Clin. Invest. 66:892-900, Weisgraber et al., 1983, J. Biol. Chem. 258: 2508-2513, Franceschini et al., 1985, Atherosclerosis 58: 159-174, Franceschini et al., 1987, Arteriosclerosis 7:426-435). Apo A-I Milano homodimers were found to reduce intimal thickening in cholesterol fed rabbits (Ameli et al., 1994, Circulation, 90: 1935-41 and Soma et al., 1995, Cir. Res. 76:405-11). In ApoE deficient mice, atherosclerotic lesions were reduced by both multiple low dose and single high dose Apo A-I Milano:lipid complexes (Shah et al., 1998, Circulation 97: 780-85 and Shah et al., 2001, Circulation 103:3047-50). Plaque regression in rabbits was also demonstrated with single local infusions of Apo A-I Milano:phospholipid complexes in doses of 500 mg and 1000 mg of protein per rabbit. (Chiesa et al., 2002, Cir. Res. 90:974-80). The lesions induced in the rabbit model are largely comprised of macrophages and not representative of the more complex lesions in humans. Therefore, it is uncertain if analogous treatments would be effective for the complicated plaques found in human atherosclerosis. (Li et al., 1999, Arterioscler Thromb Vasc Biol 19:378-383 and Shah et al., 2001, Circulation 103:3047-50).
Yet despite the improved understanding of the pathophysiology of myocardial infarction and developments in HDL therapy, safe and effective doses, dosing regimens and pharmaceutical formulations for the prophylactic and therapeutic use of Apo A-I Milano or Apo A-I Milano:lipid complexes in humans are still desired.